bardoxolone methyl (RTA 402) / Kyowa Kirin, Biogen - LARVOL DELTA

Targeting the Keap1-Nrf2 Axis in COPD: Comparative analysis of electrophilic and peptide-based Nrf2 activators in airway and immune cells. (PubMed, Eur J Pharmacol) - "These results confirm that the Nrf2 pathway is compromised in COPD and support selective Nrf2 activation-particularly via peptide-based approaches-as a promising therapeutic strategy to mitigate oxidative and inflammatory injury in the disease."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CXCL8 • IL6 • KEAP1 • MMP9 • NFE2L2 • NQO1

The Analgesic Effects of Nrf2 Activators in Chemotherapy-Induced Neuropathic Pain: Evidence from Animal Studies and Consequences for Translation into Clinical Trials. (PubMed, Int J Mol Sci) - "Chemotherapy-induced neuropathic pain (CINP) can be caused by several chemotherapeutic drugs, including paclitaxel, oxaliplatin, and vincristine, which is difficult to treat with several drugs, including antidepressants and anticonvulsants...Several Nrf2 activators, including tempol, oltipraz, rosiglitazone, pristimerin, cannabidiol, daidzein, bardoxolone methyl, curcumin, resveratrol, and mitoquinone, demonstrated analgesic effects in CINP animal models. Furthermore, in clinical studies, curcumin demonstrated significant efficacy in reducing vincristine-induced neuropathy in pediatric leukemia patients, while the combined administration of alpha-lipoic acid with ipidacrin hydrochloride prevented paclitaxel-induced motor neuropathy and improved axonal function in breast cancer patients. Thus, the purposes of our review article were to summarize the analgesic effects of Nrf2 activators and the patho-mechanisms of Nrf2 in CINP animal, and then the consequences for clinical..."

Journal • Review • Breast Cancer • Hematological Malignancies • Leukemia • Neuralgia • Oncology • Pain • Pediatrics • Solid Tumor

Discovery of novel Keap1-targeting hydrophobic tag (HyT) tethering degraders with potent Nrf2 activation activity. (PubMed, Eur J Med Chem) - "Mechanistic studies revealed a unique dual-pathway degradation process involving the ubiquitin-proteasome system and the autophagy-lysosome pathway. Our findings not only establish HyTTD as a viable degradation strategy for Keap1 but also identify NBE5 as a promising therapeutic candidate for redox-related pathologies such as inflammatory bowel disease."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Targeted Protein Degradation • CRBN • KEAP1

NRF2 activators and the inhibitor of nuclear export, selinexor, restrict coronaviruses by targeting a network involving ACE2, TMPRSS2, and XPO1 through an NRF2-independent mechanism. (PubMed, Commun Biol) - "We assessed the potential of the NRF2 activators 4-octyl itaconate (4OI), bardoxolone (BARD), and sulforaphane (SFN), and the exportin-1 (XPO1) blocker selinexor (SEL) to inhibit highly pathogenic (SARS-CoV-2) and seasonal (hCoV-229E) coronaviruses in cellular models. XPO1 knock-down reduces CoV-229E replication and reveals that efficacy of the compounds against CoV-229E depends on XPO1 expression in the order SEL > 4OI > SFN > BARD, suggesting that especially BARD restricts hCoV-229E via another, unknown, target. Taken together, these results suggest that "NRF2 activators" can restrict human coronaviruses by targeting an NRF2-independent network involving ACE2, TMPRSS2, and XPO1."

IO biomarker • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation • XPO1

Treadmill Exercise Attenuates CUMS-Induced Depressive Behaviors by Modulating the UPRmt via the Nrf2/Keap1 Pathway. (PubMed, Brain Res Bull) - "The treadmill exercise activates the Nrf2/Keap1 pathway in the hippocampus, thereby reducing CUMS-induced excessive and dysregulated endoplasmic reticulum stress (UPRmt) in an Nrf2-dependent manner, which leads to a recovery of mitochondrial function, suppression of oxidative stress, and improvement of depressive-like behaviors."

Journal • CNS Disorders • Depression • Metabolic Disorders • Mood Disorders • Psychiatry • ATF5 • HSPD1 • LONP1 • NQO1

Interleukin-1β-induced arthritis involves chondrocyte oxiapoptophagy. (PubMed, Korean J Physiol Pharmacol) - "CDDO-Me, an inhibitor of the NF-κB pathway, suppressed the IL-1β-induced expression of CH25H, CYP7B1, caspase-3, and beclin-1, as well as ROS production in chondrocytes. Collectively, these findings consistently indicate that IL-1β-induced articular cartilage degeneration is associated with chondrocyte oxiapoptophagy via the NF-κB signaling pathway."

Journal • Immunology • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology • BECN1 • CASP3 • IL1B • MAP1A • MMP1 • MMP13 • MMP3

Neuroprotective Effects of ZiYin XiFeng Formula Against Parkinson's Disease via Nrf2/SLC7A11/GPX4-Mediated Ferroptosis Inhibition. (PubMed, J Ethnopharmacol) - "ZYXF confers neuroprotection in PD by suppressing ferroptosis through activation of the Nrf2/SLC7A11/GPX4 pathway."

Journal • CNS Disorders • Hematological Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • GPX4 • SLC7A11

Effects of the Pharmacological Modulation of NRF2 in Cancer Progression. (PubMed, Medicina (Kaunas)) - "In contrast, NRF2 activators, such as bardoxolone methyl (CDDO-Me), sulforaphane, and dimethyl fumarate, exhibit chemopreventive effects by enhancing detoxification and mitigating oxidative DNA damage during early tumorigenesis...Therefore, understanding the temporal and contextual effects of NRF2 signaling is crucial for therapeutic design. The aim of this review is to examine how pharmacological modulation of NRF2 influences the invasive and metastatic dimensions of tumor progression, in addition to discussing its potential integration into TNM-based prognostic and treatment frameworks."

Journal • Review • Oncology • KEAP1 • NFE2L2

Synthetic Oleanane Triterpenoids Reduce Tumor Growth and Promote an Anti-Tumor Immune Response Independent of Cancer KEAP1 Mutational Status. (PubMed, Antioxidants (Basel)) - "Similarly, subcutaneous KEAP1 KO tumors were larger and more immune-suppressed compared to WT tumors. Both CDDO-Me and omaveloxolone reduced the tumor burden and improved immune cell phenotypes within the TIME independent of KEAP1 mutational status."

Journal • Lung Cancer • Oncology • Solid Tumor • KEAP1

NRF2 upregulation by CDDO-Me protects AC16 human cardiomyocytes against doxorubicin-induced toxicity. (PubMed, Biomed Pharmacother) - "RNA-seq analysis was also utilised to highlight the molecular mechanisms underpinning the effects DOX in AC16 cells and the CDDO-mediated mitigation of cardiotoxicity. This study provides novel insight into NRF2 dynamics in the widely utilised AC16 cells whilst further elucidating the molecular mechanisms contributing to DOX cardiotoxicity and potential NRF2-orchestrated defence."

Journal • Cardiovascular • Oncology • Pancreatic Cancer • Solid Tumor • KEAP1 • NFE2L2

Effect of bardoxolone methyl on the lower reproductive tract microbiome in turkey breeder hens. (PubMed, Front Physiol) - "These findings indicate that bardoxolone methyl treatment can finetune microbial functional capacity without destabilizing overall community structure. The results also highlight the importance of considering tissue-specific differences and functional potential when investigating reproductive function."

Journal • Infertility • Inflammation

Rodent-specific induction of cholestasis and cholangioma through the reduction of bile salt export pump by bardoxolone methyl. (PubMed, J Toxicol Sci) - "These results strongly suggest that the effects of bardoxolone methyl on the hepatobiliary system differ among animal species, especially between rodents and non-rodents. In conclusion, the risk of cholestasis and cholestasis-derived carcinogenicity associated with bardoxolone methyl are expected to be quite low in humans."

Journal • Preclinical • Biliary Cancer • Cholangiocarcinoma • Cholestasis • Hepatology • Liver Failure • Oncology • Solid Tumor

Bardoxolone methyl (Bard)-mediated strong suppression of calcium oxalate crystal formation in renal crystal recurrence model. (PubMed, Sci Rep) - "Preadministration of bardoxolone methyl (Bard), a potent Nrf2 activator, significantly suppressed recurrent CaOx crystal formation. These findings strongly suggest the existence of an interaction between oxidative stress responses and renal crystal recurrence, highlighting the potential of Nrf2 activation as a preventive strategy for recurrent stone formation."

Journal

Bardoxolone methyl triggers Ferroptosis in cardiomyocytes. (PubMed, Hum Exp Toxicol) - "Mechanistically, Bardo suppressed SLC7A11 and GPX4 expression while elevating ROS, ferrous ions, and MDA levels. Ultrastructural analysis further revealed mitochondrial volume reduction, disrupted cristae, and increased membrane density.DiscussionThese findings establish that Bardo induces ferroptosis in cardiomyocytes, potentially explaining the cardiotoxic effects observed in clinical trials."

Journal • Cardiovascular • Diabetic Nephropathy • Nephrology • Renal Disease • GPX4 • HMOX1 • NQO1 • SLC7A11

Role of Nitric Oxide and Nrf2 to Counteract Vascular Endothelial Dysfunction Induced by Periodontal Pathogens Using HUVECs. (PubMed, Cells) - "Treatments with L-Sepiapterin and CDDO-Me restored NO bioavailability, reduced oxidative and inflammatory responses, normalized metabolic gene expression, and attenuated apoptosis, with CDDO-Me showing more promising effects. This study provides the mechanistic insight linking periodontal polybacterial infection to endothelial dysfunction and metabolic impairment such as diabetes, suggesting that redox-modulating strategies such as L-Sepiapterin and CDDO-Me may help prevent vascular damage associated with periodontal disease."

Journal • Dental Disorders • Diabetes • Infectious Disease • Inflammation • Metabolic Disorders • Periodontitis • TLR4

Optical pooled screens identify activation of NRF2 as a novel therapeutic target in ALS/FTD (ALS-MND 2025) - "We next applied antisense oligonucleotides targeting KEAP1 and UBE2M, and small molecules, including bardoxolone-methyl, to activate NRF2. OPS in FUS-P525L patient-derived fibroblasts led to the discovery of key regulators of the NRF2 pathway, including CAND1, KEAP1, and UBE2M, whose downregulation restored the FUS nucleocytoplasmic ratio. These genes are central to the neddylation pathway, which governs both autophagy and NRF2-driven cellular stress responses. Complete knock-out or dCas9-mediated inhibition of CAND1, KEAP1, and UBE2M in fibroblasts and iPSC-derived neurons activated the NRF2 signaling pathway, boosted autophagy through the KEAP1-NRF2-p62 loop, and rescued nuclear FUS localization."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Cognitive Disorders • Dementia • Frontotemporal Lobar Degeneration • FUS • UBE2M

The Atpase Domain of LONP1 Is Necessary for Mitochondrial Protein Solubility and the Viability of Acute Myeloid Leukemia (AML) Cells (ASH 2023) - "Bardoxolone methyl (CDDO-Me) is a synthetic triterpenoid that inhibits the ATPase activity of LONP1 by binding to an allosteric site near the ATPase domain of the enzyme...Selective inhibition of this domain leads to mitochondrial protein aggregation, impaired mitochondrial respiration and AML cell death. Thus, inhibiting the ATPase domain of LONP1 may be a novel therapeutic strategy for AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • CD34 • LONP1

Local Activation of Nrf2 Inhibits Arteriovenous Fistula Stenosis in Mice (KIDNEY WEEK 2025) - "However, a single higher dose of either bardoxolone (1 μg/kg) or omaveloxolone (2 μg/kg) was enough to improve patency. Bardoxolone methyl reduced the volume of the stenotic lesion from 0.4 mm 3 to 0.2 mm 3 (Fig 1). Conclusion Our results suggest that local Nrf2 activation at the time of AVF creation potentially improves maturation rates by inhibiting stenosis."

Preclinical • Cardiovascular

The Mitochondrial Unfolded Protein Response (UPRmt) Is Upregulated in Acute Myeloid Leukemia (AML) and Inhibiting the UPRmt Protease, LONP1, Leads to Mitochondrial Protein Aggregation and Cell Death Selectively in AML (ASH 2024) - "Genetic depletion and chemical inhibition (Omaveloxolone and Bardoxolone methyl) of LONP1 increased mitochondrial protein aggregation in AML cell lines and primary AML samples with high LONP1 but not normal cells or AML samples with low LONP1 and low mitochondrial protein import. In summary, a subset of AML patients have increased mitochondrial protein import and upregulate UPRmt as a protective response. Targeting UPRmt and the processing of newly imported mitochondrial proteins at the level of LONP1 leads to increased mitochondrial protein aggregation and cell death in AML while sparing normal hematopoietic cells in vitro and in vivo."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • LONP1

Human coronavirus OC43 infection in human cerebral organoids: novel insights on pathogenesis and potential therapeutic interventions. (PubMed, J Biomed Sci) - "Conclusively, HCOs infected with HCoV-OC43 offer valuable insights into the pathogenesis of HCoVs in central nervous system (CNS), and might serve as a tool for developing novel therapeutic strategies for HCoVs infections, including COVID-19, especially on exploring treatment candidates."

Journal • CNS Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease

Identification and Verification of Immune Metabolism-Related Biomarkers and Immune Infiltration Landscape for Pediatric Opsoclonus Myoclonus Ataxia Syndrome in Neuroblastoma. (PubMed, CNS Neurosci Ther) - "Four immune metabolism-associated diagnostic genes were identified, including TRAF3IP2, RIPK1, KEAP1, and DPP4 for OMAS."

Biomarker • Journal • Ataxia • Movement Disorders • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • KEAP1 • RIPK1 • TRAF3IP2

KEAP1 C151 active site catalysis drives electrophilic signaling to upregulate cytoprotective enzyme expression. (PubMed, Redox Biol) - "NRF2 activators in clinical use and trials (omaveloxolone, bardoxolone methyl, and sulforaphane) readily compete with monobromobimane for C151. Overall, this work suggests enzymatic catalysis is the primary reason that C151 acts as a sensor cysteine for therapeutic, electrophilic NRF2 activators, highly favoring reaction with C151 over other cellular cysteines. The kinetic targeting of electrophiles such as sulforaphane and omaveloxolone to the C151 active site provides an explanation for how electrophilic compounds can be selective pharmacological agents."

Journal • Inflammation • KEAP1

Development of a leucine aminopeptidase-activatable co-prodrug from CDDO-Me and ligustrazine for synergistic treatment of liver injury. (PubMed, Bioorg Chem) - "Furthermore, CHL reduced p-p65 expression by 5-fold, indicating its effective inhibition of NF-κB transcriptional activity and thereby alleviating inflammatory responses. Therefore, the LAP-activable co-prodrug CHL holds promising potential as a candidate for the synergistic treatment of liver injury."

Journal • Hepatology • Inflammation • Liver Cancer • Liver Failure • Oncology • Solid Tumor • NQO1 • RELA

Investigating the Potential of CDDO-Me as an HMGB1 Inhibitor in Mitigating Cerebral Ischemia-Reperfusion Injury. (PubMed, J Neuroimmune Pharmacol) - "Further virtual mutagenesis and binding free energy calculations identified F38 and F89 in the A-box as key residues involved in HMGB1-CDDO-Me interaction. These findings indicated that CDDO-Me can improve stroke-induced inflammatory damage through direct binding HMGB1 and negative regulation of HMGB1-TLR4 downstream cytokine signaling activity."

Journal • Cardiovascular • CNS Disorders • Diabetic Nephropathy • Inflammation • Ischemic stroke • Nephrology • Renal Disease • Reperfusion Injury • HMGB1 • TLR4

Synthesis and Biological Profile of Omaveloxolone: The Cornerstone for Friedreich Ataxia Treatment. (PubMed, Int J Mol Sci) - "Through these mechanisms, OMA contributes to tissue protection and inflammation reduction in patients with FA. The review also highlights future perspective, focusing on the challenges associated with OMA reprofiling through innovative drug delivery approaches and its potential repurposing for diseases beyond FA."

Journal • Review • Ataxia • Friedreich ataxia • Inflammation • Metabolic Disorders • Movement Disorders